RESUMO
A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), ß-(compounds 1, 3, 4, 7), α1/ß-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.
Assuntos
Antagonistas Adrenérgicos/síntese química , Desenho de Fármacos , Xantonas/química , Antagonistas Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Concentração Inibidora 50 , Masculino , Agregação Plaquetária/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa/química , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/metabolismo , Relação Estrutura-Atividade , Verapamil/química , Xantonas/metabolismo , Xantonas/farmacologiaRESUMO
A series of 18 new 5-[3-(4-aryl-1-piperazinyl)propoxy]coumarin derivatives from the corresponding bromoalkyl derivatives have been designed and synthesized by us using a microwave-assisted protocol. Radioligand binding assays of this series of compounds as well as a previously synthesized series of 17 structurally-similar compounds showed that six systems have very high affinities to the 5-HT1A receptor (0.3-1.0 nM) and good selectivity against the 5-HT2A receptor. Molecular docking, structural studies and structure-activity relationship studies were used to gain more insight into the atomistic details of ligand binding and rationalize the obtained results.
